16-67658929-G-C

Variant names:

• chr16-67658929-G-C
• rs72547495
• NM_001082486.2:c.644C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001082486.2(ACD):​c.644C>G​(p.Thr215Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T215S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACD NM_001082486.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001653
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.48
• Publications: 0 publications found

Genes affected

ACD (HGNC:25070): (ACD shelterin complex subunit and telomerase recruitment factor) This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I. [provided by RefSeq, Jul 2008]

ACD Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal dominant 6

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hereditary isolated aplastic anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13648918).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082486.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	NM_001082486.2	MANE Select	c.644C>G	p.Thr215Arg	missense splice_region	Exon 7 of 12	NP_001075955.2
	ACD	NM_022914.3		c.635C>G	p.Thr212Arg	missense splice_region	Exon 7 of 12	NP_075065.3
	ACD	NM_001410884.1		c.644C>G	p.Thr215Arg	missense splice_region	Exon 7 of 11	NP_001397813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	ENST00000620761.6	TSL:1 MANE Select	c.644C>G	p.Thr215Arg	missense splice_region	Exon 7 of 12	ENSP00000478084.1
	ACD	ENST00000695659.1		c.644C>G	p.Thr215Arg	missense splice_region	Exon 7 of 12	ENSP00000512089.1
	ACD	ENST00000219251.13	TSL:2	c.635C>G	p.Thr212Arg	missense splice_region	Exon 7 of 12	ENSP00000219251.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461274 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726906

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111730

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T301R variant (also known as c.902C>G), located in coding exon 7 of the ACD gene, results from a C to G substitution at nucleotide position 902. The threonine at codon 301 is replaced by arginine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.83
DANN	Benign	0.85
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
PhyloP100		-1.5
PrimateAI	Benign	0.26	T
REVEL	Benign	0.11
Sift4G	Benign	0.097	T
Polyphen		0.93	P
Vest4		0.24
MutPred		0.42		Gain of methylation at T301 (P = 0.0192)
MVP		0.24
MPC		0.17
ClinPred		0.27	T
GERP RS		-9.9
PromoterAI		-0.028	Neutral
Varity_R		0.27
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72547495; hg19: chr16-67692832;